EP 1963354 B1 20091209 - HIGH PURITY 17alfa-CYANOMETHYL-17beta-HYDROXY-ESTRA-4,9-DIENE-3-ONE AND PROCESS FOR THE SYNTHESIS THEREOF
Title (en)
HIGH PURITY 17alfa-CYANOMETHYL-17beta-HYDROXY-ESTRA-4,9-DIENE-3-ONE AND PROCESS FOR THE SYNTHESIS THEREOF
Title (de)
HOCHREINES 17alfa-CYANOMETHYL-17beta-HYDROXYÖSTRA-4,9-DIEN-3-ON UND VERFAHREN ZU DESSEN SYNTHESE
Title (fr)
17alfa-CYANOMETHYL-17beta-HYDROXY-ESTRA-4,9-DIENE-3-ONE DE PURETE ELEVEE ET SON PROCEDE DE SYNTHESE
Publication
Application
Priority
- HU 2006000091 W 20061011
- HU P0501132 A 20051205
Abstract (en)
[origin: US2008287404A1] The invention relates to a new process for the synthesis of high purity 17alpha-cyanomethyl-17beta-hydroxy-estra-4,9-diene-3-one (further on dienogest) of formula (I) from 3-methoxy-17-hydroxy-estra-2,5(10)-diene of formula (V). The invention relates also to the high purity 17alpha-cyanomethyl-17beta-hydroxy-estra-4,9-diene-3-one and pharmaceutical compositions containing that as active ingredient. The pharmaceutical compositions according to this invention contain high purity dienogest of formula (I) in which the total amount of impurities is less than 0.1%, while the amount of 4-bromo-dienogest is under the detection limit (0.02%) as active ingredient or at least one of the active ingredients and auxiliary materials, which are commonly used in practice, such as carriers, excipients or diluents. According to our invention the dienogest of formula (I) is synthesized the following way: i) 3-methoxy-17-hydroxy-estra-2,5(10)-diene of formula (V) is reacted with aluminum isopropylate in the presence of cyclohexanone in an inert organic solvent under heating; ii) the so obtained 3-methoxy-estra-2,5(10)-diene-17-one of formula (IV) is reacted with cyanomethyl lithium at a temperature between 0 and -30° C.; iii) the obtained 3-methoxy-17alpha-cyanomethyl-17beta-hydroxy-estra-2,5(10)-diene of formula (III) is reacted with a strong organic acid in tetrahydrofuran solution; iv) the obtained 17alpha-cyanomethyl-17beta-hydroxy-estr-5(10)-ene-3-one of formula (II) is reacted with 1-1.5 equivalent of pyridinium tribromide in pyridine solution at a temperature between 0 and 60° C., then the obtained crude dienogest of formula (I) is purified by recrystallization and preparative HPLC.
IPC 8 full level
C07J 41/00 (2006.01)
CPC (source: EP US)
A61P 5/34 (2018.01 - EP); A61P 15/00 (2018.01 - EP); A61P 15/18 (2018.01 - EP); C07J 41/0094 (2013.01 - EP US)
Designated contracting state (EPC)
AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR
Designated extension state (EPC)
HR
DOCDB simple family (publication)
US 2008287404 A1 20081120; US 8314145 B2 20121120; AT E451383 T1 20091215; AU 2006323005 A1 20070614; AU 2006323005 B2 20130530; BR PI0619428 A2 20111004; BR PI0619428 B1 20210217; BR PI0619428 B8 20210525; CA 2631748 A1 20070614; CA 2631748 C 20131203; CN 101360757 A 20090204; CN 101360757 B 20110720; CY 1110063 T1 20150114; DE 602006011052 D1 20100121; DK 1963354 T3 20100412; EA 014558 B1 20101230; EA 200801508 A1 20081030; EP 1963354 A2 20080903; EP 1963354 B1 20091209; ES 2338047 T3 20100503; HR P20100102 T1 20100430; HU 0501132 D0 20060130; HU P0501132 A2 20070628; IL 191915 A0 20081229; IL 191915 A 20160421; JP 2009518377 A 20090507; JP 5399711 B2 20140129; MX 2008007243 A 20081022; PL 1963354 T3 20100531; PT 1963354 E 20100106; SI 1963354 T1 20100331; UA 91390 C2 20100726; WO 2007066158 A2 20070614; WO 2007066158 A3 20070809
DOCDB simple family (application)
US 9620906 A 20061011; AT 06808800 T 20061011; AU 2006323005 A 20061011; BR PI0619428 A 20061011; CA 2631748 A 20061011; CN 200680051598 A 20061011; CY 101100088 T 20100129; DE 602006011052 T 20061011; DK 06808800 T 20061011; EA 200801508 A 20061011; EP 06808800 A 20061011; ES 06808800 T 20061011; HR P20100102 T 20100226; HU 2006000091 W 20061011; HU P0501132 A 20051205; IL 19191508 A 20080603; JP 2008543921 A 20061011; MX 2008007243 A 20061011; PL 06808800 T 20061011; PT 06808800 T 20061011; SI 200630561 T 20061011; UA A200808851 A 20061011